8-68015357-C-T

Variant names:

• chr8-68015357-C-T
• rs4512367
• NM_024870.4:c.142-2489C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024870.4(PREX2):​c.142-2489C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,002 control chromosomes in the GnomAD database, including 17,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.43 (17389 hom., cov: 33)
• Consequence: PREX2 NM_024870.4 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.369

Genes affected

PREX2 (HGNC:22950): (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2) The protein encoded by this gene belongs to the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger (PREX) family, which are Dbl-type guanine-nucleotide exchange factors for Rac family small G proteins. Structural domains of this protein include the catalytic diffuse B-cell lymphoma homology and pleckstrin homology (DHPH) domain, two disheveled, EGL-10, and pleckstrin homology (DEP) domains, two PDZ domains, and a C-terminal inositol polyphosphate-4 phosphatase (IP4P) domain that is found in one of the isoforms. This protein facilitates the exchange of GDP for GTP on Rac1, allowing the GTP-bound Rac1 to activate downstream effectors. Studies also show that the pleckstrin homology domain of this protein interacts with the phosphatase and tensin homolog (PTEN) gene product to inhibit PTEN phosphatase activity, thus activating the phosphoinositide-3 kinase (PI3K) signaling pathway. Conversely, the PTEN gene product has also been shown to inhibit the GEF activity of this protein. This gene plays a role in insulin-signaling pathways, and either mutations or overexpression of this gene have been observed in some cancers. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREX2	NM_024870.4	c.142-2489C>T		intron_variant	Intron 1 of 39	ENST00000288368.5	NP_079146.2
PREX2	NM_025170.6	c.142-2489C>T		intron_variant	Intron 1 of 23		NP_079446.3
PREX2	XM_047422267.1	c.7-2489C>T		intron_variant	Intron 1 of 39		XP_047278223.1
PREX2	XM_047422268.1	c.142-2489C>T		intron_variant	Intron 1 of 27		XP_047278224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREX2	ENST00000288368.5	c.142-2489C>T		intron_variant	Intron 1 of 39	1	NM_024870.4	ENSP00000288368.4
PREX2	ENST00000529398.5	n.169-2489C>T		intron_variant	Intron 1 of 23	1
PREX2	ENST00000517617.1	n.48-6679C>T		intron_variant	Intron 1 of 23	2

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65741 AN: 151884 Hom.: 17343 Cov.: 33

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.414

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.433 AC: 65845 AN: 152002 Hom.: 17389 Cov.: 33 AF XY: 0.430 AC XY: 31981 AN XY: 74290

Gnomad4 AFR AF: 0.751

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.416

Alfa AF: 0.314 Hom.: 14563

Bravo AF: 0.449

Asia WGS AF: 0.393 AC: 1365 AN: 3476

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Lip and oral cavity carcinoma Other:1

Nov 02, 2015

Department of Biological Science, Sunandan Divatia School of Science, NMIMS University

Significance: association

Review Status: no assertion criteria provided

Collection Method: case-control

The frequency of the homozygous WT and SNP genotypes was higher in the oral cancer patients in comparison to controls implying the role of this genotype in predisposition of oral cancer while the heterozygous genotype frequency was higher in controls indicating decreased risk to oral cancer. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.8
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4512367; hg19: chr8-68927592;